Consensus on the clinical application of the acute levodopa challenge test in Parkinson’s disease (2025)

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. The pathological hallmark of PD is the degeneration of dopaminergic neurons in the substantia nigra, accompanied by abnormal accumulation of α-synuclein.[1] Levodopa responsiveness plays an important role in the diagnosis and treatment of PD. The acute levodopa challenge test (ALCT) serves as an easy and quantifiable procedure to assess dopaminergic responsiveness and has been widely used in clinical practice. To ensure consistency and standardize the indications, protocols, and interpretation in the clinical use of the ALCT, this expert consensus was developed on the basis of a comprehensive review of the literature and expert discussion, providing practical guidance for neurologists and other health care professionals involved in the care of patients with PD. The relevant literature published before January 2025 was reviewed. The electronic databases that were searched included PubMed, Embase, Web of Science, and the Cochrane Library. This consensus classifies the quality of evidence and the strength of recommendations based on the grading system developed by the Oxford Centre for Evidence-Based Medicine.[2] Each recommendation was further evaluated through an anonymous Delphi method using a 1–9 Likert scale. A total of 49 experts in the field participated. Strong consensus was defined as ≥80% of panelists rating an item 7–9; consensus was defined as 70–79% rating an item 7–9; and no consensus otherwise. The complete version of the consensus is provided in the Supplementary Files, https://links.lww.com/CM9/C735. Indications for the ALCT Diagnosis and differential diagnosis of PD Recommendations: (1) The ALCT is helpful for the diagnosis of PD, and for the differential diagnosis of PD and atypical parkinsonian syndrome (APS) (Grade B, Level 2a, Strong consensus). (2) Given its limitations in distinguishing early-stage PD from early APS, ALCT results should be interpreted cautiously and in combination with additional clinical data (Grade B, Level 2a, Strong consensus). Some PD patients show limited dopaminergic responsiveness, particularly in early-stage PD, tremor-dominant PD, or the postural instability and gait difficulty subtype, where improvement rates tend to be lower and less consistent.[3] Certain APS, such as multiple system atrophy–parkinsonian type and progressive supranuclear palsy–parkinsonian type, may show partial responsiveness during the ALCT, with response rates overlapping with those of some PD patients.[4] Prediction of chronic levodopa responsiveness Recommendations: (1) The ALCT may provide useful information for predicting chronic responsiveness to levodopa (Grade B, Level 2b, Consensus). Some untreated individuals in the early stages of PD may show minimal improvement during the ALCT, but still respond well to chronic levodopa therapy over time. (2) Its predictive value appears limited in early-stage PD, and caution should be exercised in the interpretation of the results in the context of the patient’s overall clinical presentation (Strong consensus). Providing objective evidence for adjustment of dopaminergic medications Recommendation: In clinical practice, the ALCT can be conducted to observe changes in motor and non-motor symptoms, motor complications, and adverse drug effects after levodopa administration, thereby enabling more precise tailoring of antiparkinsonian medication regimens (Strong consensus). Preoperative evaluation for deep brain stimulation Recommendations: (1) The ALCT is recommended as a critical tool for preoperative evaluation in patients who receive deep brain stimulation (DBS) (Grade D, Level 5, Strong consensus). ALCT-assessed preoperative levodopa responsiveness is strongly linked to short-term motor improvement after DBS and is an important predictor of postoperative motor benefit. Performing the ALCT before DBS enables patients and caregivers to better understand the potential symptomatic improvement and have realistic treatment expectations. (2) The ALCT provides limited predictive value for the therapeutic efficacy of DBS for severe dyskinesia, motor fluctuations, and medication-refractory tremor (Grade B, Level 2b, Consensus). Assessment Procedures and Methodology for the ALCT Pre-assessment preparation Recommendations: (1) Before conducting the ALCT, clinicians should confirm that the patient meets appropriate indications and does not have contraindications or confounding conditions that might affect the test (Strong consensus). A comprehensive evaluation should be conducted to identify any contraindications, including drug contraindications, severe orthostatic hypotension, active psychiatric symptoms, or severe gastrointestinal disorders, to minimize the risk of serious adverse events during testing. In addition, patients with advanced dementia, severe musculoskeletal or neuromuscular disorders, or coexisting neurological or systemic diseases that may interfere with test accuracy of the assessment should undergo thorough clinical evaluation to determine their suitability for ALCT. Before the assessment, patients should be informed of the potential side effects and risks, and written informed consent should be obtained. (2) It is generally recommended to discontinue compound levodopa and other antiparkinsonian agents for at least 12 hours before testing. For medications with long half-lives, the withdrawal time should be adjusted based on the drug’s half-life and the patient’s condition (Strong consensus). In clinical practice, prolonged withdrawal is rarely implemented due to the risk of inducing severe “OFF” states—particularly in patients with advanced disease or long disease duration—who may not tolerate the interruption. (3) Pretreatment with domperidone or mosapride could be considered to reduce the risk of levodopa-induced gastrointestinal side effects in patients with potential gastrointestinal intolerance, such as nausea and vomiting; however, caution should be taken because of the potential cardiotoxic effects of domperidone (Strong consensus). Types and dosages of levodopa Recommendations: (1) For patients with potential risks or adverse events, a stepwise dose-escalation strategy is recommended to reduce side effects and improve tolerability (Grade B, Level 2b, Strong consensus). Compared with a single-dose protocol, an acute stepwise challenge test with levodopa, which starts with a low dose of 100 mg of levodopa and gradually increases the dosage to 150 mg, 200 mg, or other appropriate dosage according to the patient’s clinical improvement and adverse effects, allows for a more comprehensive evaluation of dopaminergic responsiveness at multiple dose levels, while improving tolerability and reducing the likelihood of adverse events at the same time.[5] (2) A standardized fixed-dose regimen is recommended to ensure consistency in evaluation when appropriate. Based on current evidence, the recommended dose for ALCT is 200–250 mg of levodopa in most cases. In drug-naïve patients, an initial levodopa dose of 100 mg may be used, with stepwise escalation to a dose of 200–250 mg if needed and tolerated. In some cases, dosing may also be guided by the patient’s usual morning levodopa equivalent dose (LED), with or without a 20–50% increase (Strong consensus). For diagnostic and differential diagnostic purposes, a standardized and fixed dose of levodopa is recommended to correspond with cutoff values that confer high diagnostic accuracy. For preoperative DBS assessment, a levodopa dose of 200–250 mg is generally recommended. In patients with an inadequate “ON” response, a second evaluation may be conducted using a higher dose, such as up to 150% of the morning LED. In patients with motor complications, the test dose of levodopa should be individualized according to specific therapeutic goals. (3) The choice of the compound levodopa formulation and dosage should be individualized based on the clinical objective, disease stage, PD subtype, and comorbid conditions (Strong consensus). Evaluation parameters Recommendations: (1) The Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III or the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III are recommended for evaluating motor symptoms during the ALCT. Objective motor performance assessments may also be used when needed (Grade D, Level 5, Strong consensus). All evaluators should undergo standardized training and certification when using relevant clinical rating scales (e.g., the MDS-UPDRS) to minimize inter-rater variability and ensure scoring reliability. (2) In addition to motor evaluation, assessments of non-motor symptoms and motor complications may be included as needed based on the clinical context (Grade D, Level 5, Strong consensus). Non-motor symptoms such as blood pressure, orthostatic hypotension, pain, fatigue, and anxiety should be evaluated.[6] (3) Advanced centers with appropriate resources are encouraged to incorporate artificial intelligence-assisted and sensor-based assessments for enhanced quantitative evaluation (Strong consensus). Timing and time point selection for evaluation Recommendations: (1) It is preferable to conduct the ALCT in the morning under fasting conditions, although the timing can be adjusted based on the clinical objectives (Grade D, Level 5, Strong consensus). For patients with levodopa-induced dyskinesia, the evaluation can be scheduled during periods when dyskinesia is most likely to occur. In patients with end-of-dose wearing-off or those unable to tolerate prolonged medication withdrawal, the test may begin immediately after the patient enters the “OFF” state. (2) It is recommended that evaluations be performed at baseline, and at 1, 2, and 3 hours post-dose, continuing until the end of the “ON” period (generally within 4–6 hours). Time points may be adapted based on the assessment goal and patient characteristics (Grade D, Level 5, Strong consensus). However, repeated evaluations of the UPDRS motor and other scales may lead to patient fatigue and physical strain. In clinical practice, the assessment schedule may be simplified depending on the test objective; a two-point evaluation—at baseline and peak effect (typically 60 minutes post-dose or at the time point reported by the patient as reflecting their best improvement)—may be considered. For patients with a rapid or delayed onset of effect, using shorter assessment intervals (e.g., 30 minutes) or scheduling assessments according to their previous onset time may be considered; for end-of-dose patients, additional assessment time points may be added around their usual end-of-dose period as appropriate; and for patients whose assessment purpose is to fully evaluate the ON period, the assessment duration may be appropriately extended. A sample ALCT sheet is shown in Supplementary Table 1, https://links.lww.com/CM9/C735. Calculation of levodopa responsiveness In studies, reviews, and expert consensus documents involving the ALCT, levodopa responsiveness is typically quantified using the following formula, based on changes in UPDRS Part III motor scores: Improvement rate (%)=OFF-state UPDRS III score − peak ON-state UPDRS III scoreOFF-state UPDRS III score×100%. In clinical practice, the UPDRS Part III score assessed at 60 minutes post-dose is typically considered the peak “ON” score. In patients with a delayed response, the assessment time point may be adjusted according to the patient’s historical response pattern to capture the peak effect. Both the original version of the UPDRS and the MDS-UPDRS revision are accepted tools for this evaluation. Adverse events and preventive measures Recommendations: (1) Patients should be monitored closely during ALCT for levodopa-related effects and potential worsening of motor symptoms from medication withdrawal; preventive measures such as prokinetic agents may be used as appropriate (Strong consensus). The main adverse events associated with the ALCT can be grouped into two categories. The first includes adverse effects related to levodopa administration during the test, particularly when higher doses of compound levodopa formulations are used. These may include orthostatic hypotension, nausea and vomiting, and neuropsychiatric symptoms. The second category involves risks related to medication withdrawal during the pre-test preparation, such as the exacerbation of motor symptoms due to temporary discontinuation of antiparkinsonian medications. In rare cases, this may lead to a neuroleptic malignant-like syndrome. A checklist for high-risk patients can be found in Supplementary Table 2, https://links.lww.com/CM9/C735. (2) A stepwise dose-escalation protocol is advisable during the ALCT to enhance safety, allow for timely detection of adverse reactions, and improve patient tolerability (Strong consensus). Interpretation of ALCT Results Recommendations: (1) Most studies and guidelines support a 30% improvement in MDS-UPDRS Part III scores or UPDRS Part III scores as the threshold for a positive ALCT (Grade A, Level 1b, Strong consensus). The 2015 MDS diagnostic criteria define a >30% improvement in UPDRS Part III scores as “marked improvement”.[7] When applying improvement thresholds, standardization of testing conditions—such as levodopa dose, assessment tools, and timing—is critical to ensure inter-patient and intra-patient comparability. (2) The result of ALCT is influenced by disease type, PD subtype, clinical stage, and levodopa dose and should therefore be interpreted accordingly in clinical practice (Grade B, Level 2a, Strong consensus). In early-stage, drug-naïve PD patients and in certain subtypes such as the postural instability and gait difficulty subtype, the improvement rate may fall below the conventional 30% threshold. The response of tremor to levodopa is also perceived as less consistent than that of bradykinesia and rigidity. Some APS patients may also exhibit dopaminergic responsiveness, particularly in early stages. There is potential overlap in levodopa responsiveness between early PD and early APS. Interpretation should incorporate additional features such as clinical presentation, magnetic resonance imaging (MRI) findings, biomarkers, and longitudinal follow-up is recommended to assess long-duration response (LDR) over time. As a practical, safe, and quantifiable procedure, the ALCT plays an essential role not only in the diagnosis and optimization of dopaminergic therapy in PD patients but also in patient selection and outcome prediction for DBS. However, the ALCT is limited by its reliance on subjective clinical scoring. The incorporation of digital biomarkers, such as sensing technologies and artificial intelligence-based video assessment, has the potential to increase the accuracy, consistency, and reproducibility of the ALCT, facilitating its clinical utility.